Influenza virus types A and B are members of the orthomyxoviridae family of viruses that cause influenza infection. Influenza A and B viruses primarily infect the nasopharyngeal and oropharyngeal cavities and produce highly contagious, acute respiratory disease that can result in significant morbidity and high economic costs. Typical influenza viral infections in humans have a relatively short incubation period of 1 to 2 days, with symptoms that last about a week including an abrupt onset of fever, sore throat, cough, headache, myalgia, and malaise. When a subject is infected with a highly virulent strain of influenza these symptoms can progress rapidly to pneumonia and in some circumstances death. Pandemic outbreaks of highly virulent influenza present a serious risk to human and animal health worldwide.
Genetic reassortment between human and avian influenza viruses can result in a virus with a novel hemagglutinin (HA) of avian origin, against which humans lack immunity. Recombination between avian strains and human strains in coinfected individuals has given rise to recombinant influenza viruses to which immunity is lacking in the human population, resulting in influenza pandemics. In the 20th century, the pandemics of 1918, 1957 and 1968 were the result of such antigenic shifts.
Highly pathogenic avian influenza H5N1 viruses have become endemic in domestic poultry in Southeast Asia. Since early 2004, human infections with H5N1 viruses have been reported in the region with increasing frequency and high mortality rates. Highly pathogenic H5N1 influenza viruses were first recognized to cause respiratory disease in humans in 1997, when 18 documented cases, including 6 deaths, occurred following outbreaks of influenza in poultry farms and markets in Hong Kong. Two additional human H5N1 infections were identified in a family in Hong Kong in 2003. Since then, H5N1 viruses have spread to many Asian countries, as well as countries in Eastern Europe. The laboratory confirmed cases of human infection since January 2004 have had a fatality rate of greater than 50% as reported to the World Health Organization. To date, most of the human H5N1 virus infections have been due to direct transmission of the virus from infected poultry, although exceptional cases of human-to-human transmission have been reported.
The recent outbreaks of avian influenza caused by H5N1, H7N7 and H9N2 subtype influenza viruses, and their infection of humans have created a new awareness of the pandemic potential of influenza viruses that circulate in domestic poultry. The estimated economic impact of a pandemic would be up to $165 billion in the United States alone, with as many as 200,000 deaths, 730,000 hospitalizations, 42 outpatient visits, and 50 million additional illnesses.
Due to the lethality of these influenza strains in poultry, current vaccine production strategies involving growth of virus in hen's eggs are not feasible. Some approaches have focused on isolating non-pathogenic or attenuated strains of influenza that express the relevant immunogenic antigens of the potentially pandemic influenza strains. For example, naturally occurring, apathogenic strains of influenza with the H5 subtype antigen virus have been evaluated as vaccine candidates. In general, these viruses have proved difficult to grow using conventional technology, and protection is dependent on the ability of antibodies raised against the apathogenic vaccine strain to cross-react with the virulent strain of virus (Takada et al., J. Virol. 73:8303-8307, 1999; Wood et al., Vaccine 18:579-80, 2000).
A reverse genetics approach has been employed to delete a stretch of basic amino acids at the cleavage site of the HA antigen of a pathogenic H5N1 virus (A/HK/97) to develop a candidate vaccine (Li et al., J. Infect. Dis. 179:1132-1138, 1999).
Another approach has been to utilize recombinant HA (“H5”) produced in a baculovirus expression system. However, high doses of purified protein and the use of adjuvants are required to achieve a satisfactory immune response. (Treanor et al. Vaccine 19:1732-1737, 2001). Furthermore the production of protein from a baculovirus expression system in insect cells is laborious and time consuming.
Thus, there remains a need to develop vaccines that are protective against infection by influenza strains in both human and non-human populations, which can be efficiently produced and administered without reliance on viral growth in hen's eggs.